Deciphering the role of miR-187-3p/LRFN1 axis in modulating progression, aerobic glycolysis and immune microenvironment of clear cell renal cell carcinoma

Abstract

Clear cell renal cell carcinoma (ccRCC) is one of the most common malignant genitourinary cancers with high recurrence risk worldwide. Recently, multi-omics data facilitate obtaining a molecular landscape of tumor development, and were implemented to affect pathogenesis, phenotype, and prognosis of ccRCC. In this study, after screening for differential expressed microRNAs based on multiply datasets, we tested expression levels and prognostic value of miR-187-3p in ccRCC samples, and transfected miR-187-3p mimics or negative controls into ccRCC cells. Up-regulation of miR-187-3p restrains proliferation, migration and promotes apoptosis ability in human ccRCC A498 and 786O cells. In addition, Luciferase reporter assay revealed that miR-187-3p directly targets LRFN1-3’-UTR and negatively modulates LRFN1 expression. LRFN1 rescues proliferation and invasion capacities after miR-187-3p mimic transfection in vitro and in subcutaneous xenograft models. We further performed deep-sequencing technology and bioinformatics analyses to evaluate the biological functions and potential clinical implications of LRFN1 expression in ccRCC. Interestingly, LRFN1 could serve as an independent and potential biomarker for prognosis in over 1000 patients with ccRCC from multiply independent cohorts. Besides, the up-regulated LRFN1 expression prominently promoted intra-tumoral heterogeneity and immune-infiltrating microenvironment, represented by elevated M2 macrophage infiltration, CD8+ T cells activity and PD-L1 expression. In conclusion, this study revealed the tumor-specific and immunological role of miR-187-3p/LRFN1 axis in the progression and reshaping of tumor immune microenvironment of ccRCC.

Tumor-associated macrophage-derived chemokine CCL5 facilitates the progression and immunosuppressive tumor microenvironment of clear cell renal cell carcinoma

“…The immune escape and dysregulation of metabolic phenotypes play critical roles in cancer progression 36 , 37 . For example, tumor glycolysis affects the TME, which in turn is a major obstacle to the successful targeting of cancer by anti-tumor immunotherapies and other therapies 21 , 38 .…”

Multi-omics profiles refine L-dopa decarboxylase (DDC) as a reliable biomarker for prognosis and immune microenvironment of clear cell renal cell carcinoma

“…We divided the TCGA cohort into two subgroups based on the median value of DDC expression in order to keep the classification model simple and ensure universality. Then the DEGs between two subgroups were identified with the threshold of |log2(Fold Change)| >1.5 and adjusted P <0.05 using the R package “limma” ( 26 ) in the TCGA cohort. The Cluster Profiler package (version: 3.18.0) in R software was employed to analyze the Gene Ontology (GO)-identified functions of potential targets and perform Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis between subgroups.…”

Targeting HDAC6 to Overcome Autophagy-Promoted Anti-Cancer Drug Resistance

“…The TME is critical for cancer initiation and promotion. Cellular interactions involving cancer cells and immune cells can promote cancer cell progression [ 160 ]. Exosomal molecules regulated by HDAC6 can serve as targets for developing anti-cancer drugs.…”